HIV-1 infection generally induces a strong antibody response to the envelope glycoprotein (i.e., trimeric (gp160)3, cleaved to (gp120/gp41)3), the sole antigen on the virion surface. Most of the induced antibodies are ineffective in preventing infection, however, as they are either non-neutralizing or narrowly isolate-specific, and the virus replicates so rapidly that ongoing selection of neutralization-resistant mutants allows viral evolution to “keep ahead” of high-affinity antibody production (Wei et al. (2003) Nature 422:307). Moreover, much of the antibody response may be to rearranged or dissociated forms of gp120 and gp41, on which the dominant epitopes may be either in hypervariable loops or in positions occluded on virion-borne envelope trimer. A few rare “broadly neutralizing” antibodies have been detected that recognize one of three relatively conserved regions on the envelope protein: the CD4
binding site (mAb b12) (Burton et al. (1994) Science 266:1024); carbohydrates on the outer gp120 surface (mAb 2G12) (Trkola et al. (1996) J. Virol. 70:1100); and a segment of the gp41 ectodomain adjacent to the viral membrane (mAbs 2F5 and 4E10) (Muster et al. (1993) J. Virol. 67:6642; Stiegler et al. (2001) AIDS Res. Hum. Retroviruses 17:1757), often called the membrane-proximal external region (“MPER”). Understanding the molecular mechanisms of neutralization by these and other antibodies could help design immunogens to induce them.
Fusion of viral and target cell membranes initiates HIV-1 infection. Conformational changes in gp120 that accompany its binding to receptor (CD4) and co-receptor (e.g., CCR5 or CXCR4) lead to dissociation of gp120 from gp41 and a cascade of refolding events in the latter (Harrison (2005) Adv. Virus Res. 64:231). In the course of these rearrangements, the N-terminal “fusion peptide” of gp41 translocates and inserts into the target cell membrane. A proposed extended conformation of the gp41 ectodomain, with its fusion peptide thus inserted and the transmembrane anchor still in the viral membrane, has been called the “prehairpin intermediate” (Chan and Kim (1998) Cell 93:681). The prehairpin intermediate is the target of various fusion inhibitors, including T-20/Enfuvirtide, the first approved fusion-inhibiting antiviral drug (Kilby and Eron (2003) N. Engl. J. Med. 348:2228). The characteristics of the intermediate have been deduced from the properties of these inhibitors or mimicries by short gp41 fragments (Eckert et al. Cell 99:103; Root et al. (2001) Science 291:884). Subsequent rearrangements from the intermediate to the postfusion state of gp41 involve folding back of each of the three chains into a hairpin-like conformation, with two anti-parallel α-helices connected by a disulfide-containing loop. This process brings the fusion peptide and transmembrane anchor, and hence the two membranes, close together at the same end of the refolded protein.